(177) Elexacaftor/tezacaftor/ivacaftor treatment in pediatric cystic fibrosis lung disease reduces ventilation heterogeneity measured with hyperpolarized ¹²⁹Xe multiple-breath washout MRI

Background: Sensitive tools to monitor changes in early cystic fibrosis (CF) lung disease in children are needed to assess the efficacy of elexacaftor/tezacaftor/ivacaftor. The lung clearance index (LCI) measured by multiple-breath washout (MBW) can show treatment effects in pediatric CF [1] but is limited to whole-lung averages of ventilation, thereby missing regional information. Hyperpolarized ¹²⁹Xe MRI conducted in a MBW fashion (MBW Xe-MRI) yields maps of fractional ventilation (FV), a measure of percent gas clearance per breath. The coefficient of variation (CoV_FV) derived from FV maps can be used to assess spatial ventilation heterogeneity [2]. By regionally quantifying gas replacement and ventilation heterogeneity, MBW Xe-MRI can potentially provide different information about treatment response than LCI. This work assesses the ability of MBW Xe-MRI to capture changes in CF lung disease in pediatric subjects treated with elexacaftor/tezacaftor/ivacaftor.

Methods: To date, 7 subjects with median (range) age 17 (14-17.5) years underwent 2 visits each (baseline, one-month) including N₂ MBW and MBW Xe-MRI. LCI was measured using a Exhalyzer^®D MBW device (EcoMedics, Duernten, Switzerland; Spiroware 3.3.1). MBW Xe-MRI was performed as described by Couch et al. [3], where the ¹²⁹Xe dose (10% of TLC) was topped with N₂ to a volume of 1/6th TLC. CoV_FV was calculated using the standard deviation over mean of FV in one voxel compared to adjacent voxels. The Wilcoxon signed-rank test was used to determine significant changes between visits. Correlations of absolute differences in mean FV and CoV_FV against LCI were tested with a Spearman correlation.

Results: Xe-MRI (breath=1), FV, and CoV_FV maps for 3 representative subjects are shown in Figure 1A. The following values are averages from the maps. Median (IQR) CoV_FV was significantly (p=.0313) lower at one-month (0.07; 0.06-0.08) compared to baseline (0.10; 0.08-0.14). As well, absolute changes in CoV_FV between visits were found to significantly (p=.0028) and highly (r=0.96) correlate with absolute changes in LCI (Figure 1B). Median (IQR) FV did not significantly change (p=.1563) between baseline (0.36; 0.33-0.40) and one-month (0.41; 0.40-0.44) or correlate with LCI (r=-0.61, p=.1667).

Conclusions: CoV_FV detected improvements in ventilation homogeneity at one month following elexacaftor/tezacaftor/ivacaftor treatment. Absolute changes in CoV_FV correlated with LCI. The ongoing study will help clarify the relationship between this novel measure and other imaging outcomes in capturing treatment response.

Acknowledgements: Funding was provided by Canadian Institute for Health Research (CIHR) and Cystic Fibrosis Foundation (CFF).

References: [1] Ratjen F, Hug C, Marigowda G, Tian S, Huang X, Stanojevic S, Milla CE, Robinson PD, Waltz D, Davies JC; VX14-809-109 investigator group. Efficacy and safety of lumacaftor and ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial. Lancet Respir Med. 2017 Jul;5(7):557-567.
[2] Horn, FC., Marshall, H., Siddiqui, S., Horsley, S., Smith, L., & Aldag, I. et al. Ventilation heterogeneity in obstructive airways disease – comparing multi-breath washout-imaging with global lung measurements. [Abstract]. Proc Intl Soc Mag Reson Med. 2015;23.
[3] Couch MJ, Morgado F, Kanhere N, et al. Assessing the feasibility of hyperpolarized 129Xe multiple-breath washout MRI in pediatric cystic fibrosis. Magn Reson Med. 2020;84:304–311. https://doi.org/10.1002/mrm.28099.